It is likely that the enteric nervous system responds in a paracrine fashion to intraluminal stimulation by release of 5-HT by mucosal EC cells. Intrinsic and extrinsic sensory nerves express 5-HT1P/4 and 5-HT3 receptor respectively. Intestinal epithilial cells express a plasmalemmal 5HT transporter (SERT) similar to that of serotoninergic neurons, which controls the extent to which 5-HT acts as a mucosal signaling molecule. In this proposal mice lacking SERT will be used to 1. determine what compensatory changes occur in the gut of SERT- mice 2. Determine what changes in GI motility and central signaling occur in these mice and 3. Investigate additional intraluminal stimuli that can activate submucosal primary afferent neurons other than pressure distortion in guinea pig, SERT - and control mice. A combination of immunocytochemical, molecular and electrophysiological techniques will be used to address these aims. The SERT - mice model provides a hyperserotonergic model of the gut, which may represent states of disease such as IBS, infection, use of antidepressants etc.